CS cells exhibit elevated poly(ADP)ribose. Thus, one outstanding question is where in the nucleus does the poly-ADP ribose (PAR) signal originate from. The recently developed ADPr-ChAP mapping of PAR has demonstrated that oxidative damage-induced PAR mostly occurs in heterochromatin regions. Since PAR occurs on heterochromatin, we hypothesize that the heterochromatin structure provides a barrier protecting nuclear DNA from damage. Interestingly, we have found that CS- deficient cells have decreased heterochromatin, despite harboring elevated PAR on chromatin, thus potentially rendering their genomes more susceptible to genome instability. By genome-wide deep sequencing of pH2A.X, H3K9me3 and PAR, we have identified the genomic hotspots for PAR and analyzed the resulting transcriptome alterations in CS. Furthermore, we identified SETDB1, a H3K9me3 methyltransferase, as being partially responsible for the altered heterochromatin in CS-deficient cells.